Impotence or erectile insufficiency is a widespread disorder that is thought to affect about twelve percent of adult men under age forty-five, about twenty percent of men at age sixty, and about fifty-five percent of men at age seventy-five. A number of causes of erectile insufficiency, in addition to anatomical deficiencies of the penis or scrotum that preclude an erection sufficient for vaginal penetration, have been identified. These causes are psychological and physical in origin and in any individual suffering from impotence there may be more than one cause of erectile dysfunction.
Erectile dysfunction can be psychological, resulting, for example, from anxiety or depression, with no apparent somatic or organic impairment. Such erectile dysfunction, which is referred to as “psychogenic”, is responsible for about fifteen to twenty percent of cases of impotence. In other cases, the erectile dysfunction is associated with atherosclerosis of the arteries supplying blood to the penis; such dysfunction is referred to as “arteriogenic” or “atherosclerotic.” About forty to sixty percent of cases of impotence are arteriogenic in origin.
In still other cases, there is leakage from veins in the penis such that sufficient pressure for an erection can be neither obtained nor maintained. This dysfunction is referred to as “venous leakage,” or “abnormal drainage”. This condition is often exacerbated by the presence of some arteriogenic dysfunction whereby the supply of blood to the penis is impaired. In still other cases, the dysfunction is associated with a neuropathy, such as nerve damage arising from, for example, surgery or a pelvic injury, in the nervous system affecting the penis. Such a dysfunction is referred to as “neurogenic” and about ten to fifteen percent of cases of impotence are neurogenic in origin.
There is also a high incidence of erectile insufficiency among diabetics, particularly those with insulin-dependent diabetes mellitus. Erectile dysfunction in diabetics is often classified as “diabetogenic,” although the underlying dysfunction is usually neurogenic associated with neuropathy, but may be arteriogenic or neurogenic and arteriogenic. About half of diabetic males suffer from erectile insufficiency, and about half of the cases of neurogenic impotence are in diabetics.
Erectile insufficiency is sometimes a side effect of certain drugs, such as beta-blockers that are administered to reduce blood pressure in persons suffering from hypertension, or drugs administered to treat depression or anxiety. Excessive alcohol consumption has also been linked to erectile insufficiency. These forms of erectile insufficiency may be regarded as a subset of neurogenic or psychogenic insufficiency.
A number of methods to treat impotence are available. These treatments include pharmacological treatments, surgery and, in cases of psychogenic dysfunction, psychological counseling is sometimes effective.
In the rare cases, where the insufficiency is untreatable because of venous leakage, surgery can usually be employed to repair the venous lesion and thereby either cure the insufficiency or, if there remains an erectile insufficiency after repair of the venous lesion, render the insufficiency amenable to treatment by pharmacological methods. Also, penile implants, which provide a mechanic means to produce an erection sufficient for vaginal penetration, are widely used to treat impotence. In recent years, implants have been employed, especially in cases where pharmacological intervention is ineffective, which are usually cases of severe atherogenic impotence. Treatment of impotence with penile implants, however, entails serious disadvantages. Such treatment requires surgery and necessitates total destruction of the erectile tissues of the penis, forever precluding normal erection.
Pharmacological methods of treatment are also available. Such methods, however, have not proven to be highly satisfactory or without potentially severe side-effects.
VIAGRA® (sildenafil citrate, Pfizer, Inc., New York, N.Y.), taken orally, is effective for up to 80% (depending upon the severity of erectile dysfunction (ED) and/or any underlying disease) of patients to produce an adequate erection for sexual intercourse. It is effective for a broad range of causes. Successful VIAGRA® patients have normal, natural erections. VIAGRA® has no effect on libido (sexual desire) so that it will not be effective unless a man feels stimulated.
VIAGRA® suppresses the enzyme phosphodiesterase so that the erection-producing chemical cyclic guanosine monophosphate (cGMP) is not broken down, so that a normal erection occurs. cGMP is a natural vasodilator (dilates penile arteries) which relaxes the smooth muscle of penile arteries so that the relaxed smooth muscle, in combination with normal blood pressure, causes the penile arteries to dilate so that the erectile chambers are engorged with blood to produce an erection.
Men who cannot take VIAGRA® or find it ineffective are often able to achieve erections by using another treatment which produces erections directly, without sexual stimulation. This treatment uses vasodilation (vessel dilation) by means of medications (vasodilators) which dilate the penile arteries so that the erectile chambers become engorged with blood to produce an erection. These medications relax the smooth muscle of penile arteries to cause arterial dilation.
The most common vasodilator is ALPROSTADIL® (Caverjet, Edex, Schwarz Pharma USA Holdings, Inc., Wilmington, Del.). It can be injected into the base of the penis (into one of the corpora cavernosa) with a needle or inserted into the urethra in pellet form through a delivery system called MUSE (Medicated Urethral Suppository for Erection). ALPROSTADIL® is effective in over 80% of patients and MUSE for about 30% of men with erectile dysfunction. For men for whom ALPROSTADIL® is ineffective, an injected mixture of vasodilators (TRIMIX) is effective for about 62% of patients.
Men who are able to achieve a normal erection but cannot sustain it because they have venous leakage may be helped by a penile constriction band. This is a ring-like device that is fastened around the base of the penis to keep blood from escaping. A penile band called Actis is available (Vivus Corp.).
A new medication Uprima (apomorphine), taken orally, is under study. It seeks to target mechanisms in the brain to produce an erection. It has been approved in Europe for treatment of erectile dysfunction.
A topical medication Topiglan (ALPROSTADIL®) has had promising results, applied to the head of the penis to produce an erection directly, without sexual stimulation. An ointment would ease the mode of delivery while reducing the risk of adverse effects compared to injection or urethral pellet.
Two oral medications, vardenafil and tadalafil, like sildenafil (VIAGRA®), are PDE-5 inhibitors which suppress the enzyme which breaks down the natural vasodilator cGMP in order to facilitate and maintain an erection.
When two or more medications are used in combination, the treatment is called combination pharmacotherapy. When a medication is used alone, the treatment is called monotherapy. When any monotherapy fails, a combination pharmacotherapy may be effective.
Combination pharmacotherapies using at least two medications have been used experimentally with significant results. The combination of VIAGRA® and MUSE has been evaluated (Eur. Urol. 2000; 38: 30-4 and BJU. Int. 2000; 86: 469-73 and Urol. 2000; 163: 198).
Another study evaluated the benefit of oral alpha blockers (daily oral doxazosin) in combination with intracavernosal (injected) ALPROSTADIL® (Urol. 1998; 52: 739-43).
Another study (Internat. J. Impot. Res. 2002; 14(1): 50-53) combined VIAGRA® with daily oral Cardura (doxazosin).
Angiotensin (Ang) peptides are a group of regulatory peptides in the renin-angiotensin system (RAS), which helps regulate blood pressure and extracellular volume in the body. Several angiotensin peptides are known, e.g., Ang-(2-8) (angiotensin III), Ang-(3-8) (angiotensin IV), Ang II (4-8), Ang II (5-8), Ang II (1-4), Ang-(1-9), and Ang-(1-7).
Ang-(1-7) is a biologically active heptapeptide of (RAS), and its functions are often opposite to those attributed to Ang II, which is the main effector component of RAS. Ang-(1-7) may be formed from Ang II via the angiotensin converting enzyme-2 (ACE-2), or directly from Ang I by action of neutral- or prolyl-endopeptidases. The receptor for Ang-(1-7) is the G-protein-coupled receptor Mas (see Santos R. A. S., et al. (2003). PNAS, USA, 100: 8258-8263). The major activities of Ang-(1-7) are vasodilation via stimulation of nitric oxide, prostaglandins and potentiation of bradykinin activities, and antidiuresis.
Other important activities of Ang-(1-7) are known, e.g., Ang-(1-7) may be involved in learning and memory mechanisms (see, Santos, R. A. and Campagnole-Santos, M. J. (1994) Braz Med Biol Res. 27(4):1033-47; Hellner, K., et al. (2005) Mol Cell Neurosci. 29(3):427-35).
Table 1 summarizes the biological activities of Ang-(1-7) and other important angiotensins (source: Ferreira A J, and Santos R A S. (2005). Braz J Med Biol Res, 38:499-507).
TABLE 1Cardiovascular effects mediated by angiotensin receptorsAngiotensinReceptorActionsAng IIAT1Vasoconstriction and pressoreffectIncrease of inotropism andchronotropismArrhythmogenic effectRemodeling and cell proliferationThrombosis and inflammationAng IIAT2Inhibition of cell proliferationApoptosisVasodilationAng-(1-7)AT1-7(Mas)*VasodilationPotentiation of BK-inducedvasodilationAnti-arrhythmogenic effectImprovement of post-ischemiccontractile functionInhibition of cell proliferationAng-(3-8) (AngAT4(IRAP)VasodilationIV)Inhibition of cell proliferationDes-Asp1-Ang IAT1Inhibition of Ang II-induced cellproliferation*Mas-mediated actions are listed based on direct or indirect evidence (blocked by A-779).Ang = angiotensin; BK = bradykinin; IRAP = insulin-regulated aminopeptidase
The benefits of using Angiotensin-(1-7) in heart disease and its complications has been an important issue related to this heptapeptide. For example, U.S. Patent Application 2004/171584 discloses formulations comprising angiotensin-(1-7) and/or losartan for treatment of arterial hypertension and other cardiovascular diseases. In addition, U.S. Patent Application 2005/069533 discloses formulations of angiotensin-(1-7) for treating arterial hypertension, wounds, burns, erithema, tumors, alopecia, blood diseases, diabetes mellitus, sperm motility, nephropathy, gastrointestinal and gynaecological disorders, angiogenesis and angioplasty.
It is known that there are at least three different pathways to form Ang-(1-7) (see, e.g., Ferreira, A. J. and Santos, R. A. S. (2005) Braz J Med Biol Res, 38:499-507); Loot, A. E. (2005). Therapeutic perspectives of Angiotensin-(1-7) in heart failure. Thesis Dissertation. University of Groningen). Ang-(1-7) may be formed from Ang I (1-10), (i) directly, by combined action of neutral-endopeptidase and prolyl-endopeptidase (NEP and PEP), or (ii) indirectly, by hydrolysis of the intermediate Ang-(1-9) by action of angiotensin-converting enzyme and neutral-endopeptidase (ACE and NEP). Alternatively, Ang-(1-7) may be formed by hydrolysis of Ang II (1-8) by action of prolyl-carboxypeptidase, prolyl-endopeptidase and angiotensin-converting enzyme 2 (PCP, PEP and ACE2).
The sexual disturbances of the present invention are known to those skilled in the art (see, e.g., Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV), American Psychiatric Association, Washington D.C., 1994 as well as the DSM-IV Guidebook, American Psychiatric Press, Inc., Washington D.C., 1995.
Thus, although impotence is a ubiquitous problem, there are few satisfactory methods available for treating this disorder. Therefore, it is an object herein to provide methods and compositions for treating impotence.